title: Dysregulated bile acid synthesis, metabolism and excretion in a high fat-cholesterol diet-induced fibrotic steatohepatitis in rats.
abstract: OBJECTIVE
  Cholesterol over-intake is involved in the onset of nonalcoholic steatohepatitis (NASH), and hepatocellular bile acid (BA) accumulation correlates with liver injuries. However, how dietary cholesterol influences cholesterol and BA kinetics in NASH liver remains ambiguous and needs to be clarified.
  
  
  METHODS
  Molecular markers involved in cholesterol and BA kinetics were investigated at protein and mRNA levels in an already-established stroke-prone spontaneously hypertensive 5/Dmcr rat model with fibrotic steatohepatitis, by feeding a high fat-cholesterol (HFC) diet.
  
  
  RESULTS
  Unlike the control diet, the HFC diet deposited cholesterol greatly in rat livers, where 3-hydroxy-3-methylglutaryl CoA reductase, low-density lipoprotein (LDL) receptor and LDL receptor-related protein-1 were expectedly downregulated, especially at 8 and 14 weeks, suggesting that cholesterol synthesis and uptake in response to cholesterol accumulation may not be disorganized. The HFC diet did not upregulate liver X receptor-α, conversely, it enhanced classic BA synthesis by upregulating cholesterol 7α-hydroxylase but downregulating sterol 12α-hydroxylase, and influenced alternative synthesis by downregulating sterol 27-hydroxylase but upregulating oxysterol 7α-hydroxylase, mainly at 8 and 14 weeks, indicating that there were different productions of primary BA species. Unexpectedly, no feedback inhibition of BA synthesis by farnesoid X receptor occurred. Additionally, the HFC diet impaired BA detoxification by UDP-glucuronosyltransferase and sulfotransferase 2A1, and decreased excretion by bile salt export pump at 8 and 14 weeks, although it induced compensatory export by multidrug resistance-associated protein-3. The disturbed BA detoxification may correlate with suppressed pregnane X receptor and constitutive androstane receptor.
  
  
  CONCLUSIONS
  The HFC diet may accumulate BA in rat livers, which influences fibrotic steatohepatitis progression.
authors.affiliation: Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Jia
authors.forename: Hisao
authors.initials: H
authors.lastname: Naito
authors.forename: Husna
authors.initials: H
authors.lastname: Yetti
authors.forename: Hazuki
authors.initials: H
authors.lastname: Tamada
authors.forename: Kazuya
authors.initials: K
authors.lastname: Kitamori
authors.forename: Yumi
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Dong
authors.initials: D
authors.lastname: Wang
authors.forename: Yukie
authors.initials: Y
authors.lastname: Yanagiba
authors.forename: Juncai
authors.initials: J
authors.lastname: Wang
authors.forename: Katsumi
authors.initials: K
authors.lastname: Ikeda
authors.forename: Yukio
authors.initials: Y
authors.lastname: Yamori
authors.forename: Tamie
authors.initials: T
authors.lastname: Nakajima
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000096:biosynthesis* / Q000378:metabolism; D001692:Biological Transport; D002784:Cholesterol / Q000009:adverse effects*; D002791:Cholesterol, Dietary / Q000008:administration & dosage / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D005234:Fatty Liver / Q000209:etiology*; D005786:Gene Expression Regulation / Q000502:physiology; D008103:Liver Cirrhosis / Q000139:chemically induced*; D008297:Male; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats
chemical_list: D001647:Bile Acids and Salts; D002791:Cholesterol, Dietary; D012333:RNA, Messenger; D002784:Cholesterol